When kidneys fail, there are numerous toxins that accumulate in the blood. Many of these toxins are small molecules with positive or negative charge such as potassium, sodium, hydrogen, ammonium (generated from urea in the gut) and phosphate. Other toxins are uncharged organic molecules of small to large molecular weight (100-3,000 MW). Many of the small molecular weight and charged toxins affecting patients with kidney failure come into the patient through ingested food. Others, such as ammonium, are generated by passage of urea across the intestinal membranes and catalysis by bacterial urease within the gastrointestinal (GI) tract.
Organic toxins do penetrate the intestinal membranes somewhat and some are generated within the colon.
Currently the sodium form of sodium-loaded polystyrene sulfonate (PS) (Na-PS or Kayexalate® marketed by Sanofi) is taken as an oral powder in suspension for removal of potassium from the gut and from patients with high serum potassium levels. Na-PS was first approved by FDA for market in the 1960s. See FLINN R B, MERRILL J P, WELZANT W R. Treatment of the oliguric patient with a new sodium-exchange resin and sorbitol; a preliminary report. N Engl J Med. 1961 Jan. 19; 264:111-5 and Mahoney B A, Smith W A, Lo D S, Tsoi K, Tonelli M, Clase C M. Emergency interventions for hyperkalaemia. Cochrane Database Syst Rev. 2005 Apr. 18; (2):CD003235. However sodium release is a problem with this powder, especially if used for a long period. See Kovesdy C P. Management of hyperkalaemia in chronic kidney disease (CKD). Nat Rev Nephrol. 2014 Sep. 16. Hydrogen-loaded PS (H-PS) has also been tested in animal studies and shown to remove small amounts of potassium from animals, without adverse consequences but this causes a loss of serum sodium and acidosis (decrease in serum bicarbonate). See T. S. DANOWSKI, L. GREENMAN, F. M. MATEER, W. B. PARSONS, F. A. WEIGAND, H. MERMELSTEIN, AND J. H. PETERS. CARBOXYLIC CATION EXCHANGE RESIN EFFECTS IN DOGS. Journal of Clinical Investigation, p. 984-994, 1951. In Europe PS is also available in the calcium form (Ca-PS) and is marketed by Fresenius Medical Care (FMC) as Sorbisterit and is also available in Japan as Argamate (jelly type) and Kalimate (powder type). See Tomino Y, Yamazaki T, Shou I, Tsuge T, Satake K, Takeda Y, Ohtani A, Nishitani T, Kurusu A, Hamada C, Horikoshi S, Maeda K, Tanaka Y, Fukuda H, Wakabayashi M, Seto T. Dose-response to a jelly preparation of calcium polystyrene sulfonate in patients with hyperkalemia—changes in serum potassium levels with or without a RAAS inhibitor. Clin Nephrol. 2007 December; 68 (6): 379-85. This formulation may increase serum calcium levels and has a lower capacity for potassium than the sodium form due to the preference of PS for divalent cations. Fortunately the concentration of these exchangeable divalent cations in the gut is relatively low, so only about 25-50% of the capacity of the PS will be taken up by the divalent cations.
Working with Union Carbide and their joint-venture UOP, Inc. over many years, Dr. Ash advised these companies of the importance of finding cation exchangers that would be specific for binding monovalent cations and would not bind divalent cations. Such sorbents would have higher capacity for binding potassium and ammonium (from urea) during therapy of patients with kidney failure, whether used as oral sorbents or as a column used to regenerate dialysate during extracorporeal dialysis therapies. The first generation of compounds developed by Union Carbide were synthetic zeolites, which had the ability to exchange calcium or magnesium for the monovalent cations. However, the partial solubility of these compounds resulted in release of aluminum and silica, and this limited their safety in use either as oral sorbents or as dialysate regenerating compounds. After many years of research, UOP, Inc. developed zirconium cyclosilicate (ZS9), a crystalline compound with pores that are designed to optimally interact with charges on monovalent cations but sub-optimal in interactions with divalent cations (U.S. Pat. Nos. 8,802,152 and 8,808,750). ZS9 is selective in its binding for monovalent cations (potassium, sodium, hydrogen and ammonium) and thus does not become loaded with divalent cations (such as calcium and magnesium).
In sodium-hydrogen loaded form zirconium cyclosilicate has been shown to be an effective binder for potassium and ammonium in the gut (U.S. Pat. Nos. 8.802,152 and 8,808,750). Clinical trials have shown that this product can effectively remove potassium from patients when taken orally as an intestinal sorbent, decreasing the serum potassium levels by about 1 mEq/L in 48 hours, for patients with chronic kidney disease (CKD) who have high potassium levels. See Stephen R. Ash, Bhupinder Singh, Philip T. Lavin, Fiona Stavros, Henrik S. Rasmussen. Safety and Efficacy of ZS-9, a Novel Selective Cation Trap, for Treatment of Hyperkalemia in CKD Patients. Presented at ASN High Impact Abstracts Session, Nov. 11, 2013. Additionally the clinical trials showed that there was a small but significant decrease in serum urea nitrogen (BUN) level, apparently due to binding of ammonium in the gut. Because the crystal is partially loaded with hydrogen, and because there are buffers like bicarbonate in the gut, the exchange of potassium and ammonium is principally for hydrogen, and there appears to be little or no net transfer of sodium to the patient. See Ash, Stephen R., Singh, Bhupinder; Lavin, Philip; Stavros, Fiona; Rasmussen, Henrik. Safety and Efficacy of ZS-9, a Novel, Selective Potassium Trap: Results of a Phase 2 Study of the Treatment of Hyperkalemia in Patients with CKD. Accepted for publication in Kidney International, September 2014. However, ZS9 does not remove any excess sodium from the patient. For end stage renal disease (ESRD) patients with fluid overload, a system to remove sodium would be very helpful and almost all ESRD patients need a phosphate binder also.
One clinical finding in our studies of ZS9 was that patients tolerated ingestion of this inorganic sorbent very well. Ten gram doses of the very fine powder were mixed in small amounts of water and drunk from a glass. As opposed ingestion of resins such as Na-PS, there were no complaints of grittiness, malodor or poor taste. Patients generally agreed that ingestion of the powder was more comfortable than taking a large number of pre-formed tablets. This advantage also applies to other inorganic ion exchangers such as ZP and ZO (discussed below).
For FIGS. 17, 18, and 19, corresponding reference characters indicate corresponding parts throughout the several views. Although the drawings represent embodiments of the present disclosure, the drawings are not necessarily to scale and certain features may be exaggerated in order to better illustrate and explain the present disclosure.